Saleh Marwa A, El-Badry Mohamed A, R Ezz Eldin Rogy
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Department of Botany and Microbiology, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt.
J Comput Chem. 2021 Aug 15;42(22):1561-1578. doi: 10.1002/jcc.26693. Epub 2021 May 26.
Infectious diseases of bacteria and fungi have become a major risk to public health because of antibiotic and antifungal resistance. However, the availability of effective antibacterial and antifungal agents is becoming increasingly limited with growing resistance to existing drugs. In response to that, novel agents are critically needed to overcome such resistance. A new series of 6-hydroxyquinolinone 3, 4, 5a, 5b, 6a and 6b bearing different side chains were synthesized and evaluated as antimicrobials against numbers of bacteria and fungi, using inhibition zone technique. As one of these derivatives, compound 3 was identified as a potent antibacterial and antifungal agent against all tested microorganisms with good minimum inhibitory concentration values comparable to reference drugs. Molecular docking studies were performed on antibacterial and antifungal targets; microbial DNA gyrase B of Staphylococcus aureus (PDB ID: 4URO); N-myristoyltransferase of Candida albicans (PDB ID: 1IYK), respectively, to predict the most probable type of interaction at the active site of the target protein in addition to binding affinities and orientations of docked ligands. Additionally, in silico prediction in terms of detailed physicochemical ADME and toxicity profile relating drug-likeness as well as medicinal chemistry friendliness was performed to all synthesized compounds. The results indicated that a novel 4,6-dihydroxyquinolin-2(1H)-one (3) is likely to be a newly synthesized drug candidate, indicating low toxicity in addition to good in silico absorption. In order to pave the way for more logical production of such compounds, structure-activity and toxicity relationships are also discussed.
由于细菌和真菌对抗生素和抗真菌药物产生耐药性，其引发的传染病已成为公共卫生的重大风险。然而，随着对现有药物耐药性的不断增加，有效的抗菌和抗真菌药物的供应越来越有限。为此，迫切需要新型药物来克服这种耐药性。合成了一系列带有不同侧链的6-羟基喹啉酮3、4、5a、5b、6a和6b，并采用抑菌圈技术评估了它们对多种细菌和真菌的抗菌活性。作为这些衍生物之一，化合物3被鉴定为一种强效的抗菌和抗真菌剂，对所有测试微生物均具有良好的最低抑菌浓度值，与参考药物相当。分别对金黄色葡萄球菌的微生物DNA促旋酶B（PDB ID：4URO）和白色念珠菌的N-肉豆蔻酰转移酶（PDB ID：1IYK）进行了分子对接研究，以预测目标蛋白活性位点最可能的相互作用类型，以及对接配体的结合亲和力和取向。此外，还对所有合成化合物进行了关于详细物理化学ADME和毒性特征的计算机预测，包括药物相似性和药物化学友好性。结果表明，新型4,6-二羟基喹啉-2(1H)-酮（3）可能是一种新合成的候选药物，除了具有良好的计算机吸收性外，还具有低毒性。为了为更合理地生产此类化合物铺平道路，还讨论了构效关系和毒性关系。
